Social isolation

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: Social Neuroscience: Gene, Environment, Brain, Body

Social isolation

John T. Cacioppo,1 Louise C. Hawkley,1 Greg J. Norman,1 and Gary G. Berntson2

1Center for Cognitive and Social Neuroscience, University of Chicago, Chicago, Illinois. 2Department of Psychology,Ohio State University, Columbus, Ohio

Address for correspondence: John T. Cacioppo, Center for Cognitive and Social Neuroscience, University of Chicago, 5848S. University Avenue, Chicago, IL 60637. [email protected]

Social species, by definition, form organizations that extend beyond the individual. These structures evolved hand inhand with behavioral, neural, hormonal, cellular, and genetic mechanisms to support them because the consequentsocial behaviors helped these organisms survive, reproduce, and care for offspring sufficiently long that they tooreproduced. Social isolation represents a lens through which to investigate these behavioral, neural, hormonal,cellular, and genetic mechanisms. Evidence from human and nonhuman animal studies indicates that isolationheightens sensitivity to social threats (predator evasion) and motivates the renewal of social connections. The effectsof perceived isolation in humans share much in common with the effects of experimental manipulations of isolationin nonhuman social species: increased tonic sympathetic tonus and HPA activation; and decreased inflammatorycontrol, immunity, sleep salubrity, and expression of genes regulating glucocorticoid responses. Together, these effectscontribute to higher rates of morbidity and mortality in older adults.

Keywords: social isolation; social neuroscience; loneliness; gene expression; health

Introduction

Social species, by definition, form organizationsthat extend beyond the individual. These structuresevolved hand in hand with behavioral, neural, hor-monal, cellular, and genetic mechanisms to sup-port them because the consequent social behaviorshelped these organisms survive, reproduce, and carefor offspring sufficiently long that they too repro-duced, thereby ensuring their genetic legacy.

Social isolation has significant effects. About aquarter century ago, House, Landis, and Umber-son1 published a landmark review of prospectiveepidemiological studies of social isolation in hu-mans. They reported that social isolation was a sig-nificant risk factor for broad-based morbidity andmortality—a finding that subsequent research hasconfirmed.2 What was especially surprising was thatsocial isolation was as strong a risk factor for mor-bidity and mortality as smoking, obesity, sedentarylifestyle, and high blood pressure.1 The “social con-trol hypothesis” was posited to explain the effectof isolation. Social control theory holds that inter-

nalized obligations to, and the overt influence of,network members tend to discourage poor healthbehaviors and encourage good health behaviors.3

For instance, among women, direct social control(i.e., “how often does anyone tell or remind youto do anything to protect your health?”) predictedincreased physical activity three years later.4 Beingmarried is associated with an increased likelihood ofengaging in health-promoting behaviors such as ex-ercise,5–7 presumably because marital partners exertsome influence over these behaviors.8,9

There are two reasons, however, to regard thesocial control hypothesis as insufficient. First, stud-ies of isolation and health behaviors indicate thatsocial control does not explain many of the ef-fects of isolation in humans.10,11 Second, experi-mental studies in nonhuman social species indicatethat isolation has direct, deleterious physiologicaleffects. For instance, experimental studies have doc-umented that social isolation decreases the lifes-pan of the fruit fly, Drosophila melanogaster;12 in-creases neuronal damage and mortality followingexperimental stroke through the modulation of

doi: 10.1111/j.1749-6632.2011.06028.xAnn. N.Y. Acad. Sci. 1231 (2011) 17–22 c© 2011 New York Academy of Sciences. 17

Social isolation Cacioppo et al.

pro-inflammatory cytokine expression,13 increasesobesity and type 2 diabetes in mice;14 and delaysthe positive effects of running on adult neurogene-sis in rats.15 Furthermore, social isolation increasesthe activation of the sympatho-adrenomedullaryresponse to stress in rats;16 decreases theexpression of genes regulating glucocorticoid re-sponse in the frontal cortex of piglets;17 increasesbasal cortisol concentrations, and decreases lym-phocyte proliferation to mitogens in pigs;18 in-creases oxidative stress in the aortic arch of theWatanabe heritable hyperlipidemic rabbit;19 and in-creases the morning rises in cortisol in squirrel mon-keys.20 Together, these experimental studies suggestthat social isolation increases chronic sympathetictonus, oxidative stress, and HPA activation while de-creasing inflammatory control, and the expressionof genes regulating glucocorticoid responses.

Social isolation in humans

In ontogeny and phylogeny, humans need othersto survive and prosper. Animal studies of socialisolation are an important complement to humanstudies because randomization and experimentalmanipulations of isolation in humans is limited inintensity and duration due to the risk of deleteriouseffects. In addition, longitudinal studies of socialisolation in population-based samples with statis-tical controls for potential confounding variables(e.g., depressive symptomatology) have begun toidentify potential behavioral, neural, hormonal, cel-lular, and genetic effects of isolation in humans.21,22

Among the findings in this research are that (1) per-ceived social isolation is a more important determi-nant of deleterious outcomes than is the variation inobjective social isolation that is seen in population-based studies; and (2) the effects of perceived iso-lation in these longitudinal studies share much incommon with the effects of experimental manip-ulations of isolation in nonhuman social species:increased sympathetic tonus HPA activation, de-creased inflammatory control, expression of genesregulating glucocorticoid responses, and glucocor-ticoid resistance.

Humans are capable of deception, betrayal, ex-ploitation, and murder as well as empathy, compas-sion, loyalty, and prosocial behavior. Given shift-ing alliances and malleable social hierarchies, thepresence of others, even ostensive friends, may con-stitute a social threat at any moment in time. The

objective presence of others, therefore, is not suf-ficient to ensure the social connections needed forhuman survival and prosperity. Fortunately, assess-ments have been developed with which to measureperceived as well as objective isolation. Studies us-ing these assessments indicate that objective socialisolation can affect perceptions of isolation,23,24 butshow that perceived social isolation is more closelyrelated to the quality than the quantity of social in-teractions.25

When the effects of each are contrasted, perceivedsocial isolation predicts various outcomes aboveand beyond what is predicted by objective isola-tion. Beyond what is predicted by objective isolation,perceived isolation predicts greater vascular resis-tance,26 elevated blood pressure,27,28 morning risein cortisol,29 less salubrious sleep,28,30 and sedentarylifestyles.31 Perceived (but not objective) social isola-tion has also been associated with gene expression—specifically, the underexpression of genes bearingantiinflammatory glucocorticoid response elementsand overexpression of genes bearing response ele-ments for proinflammatory NK-�B/Rel transcrip-tion factors.32 This finding is paralleled by decreasesin lymphocyte sensitivity to physiological regulationby the hypothalamic pituitary adrenocortical (HPA)axis in individuals who feel socially isolated.33 To-gether with evidence of increased activity of the HPAaxis,29,34 these results suggest that the developmentof glucocorticoid resistance may result from chronicexposure to perceived social isolation.

In a longitudinal study of cognitive function-ing, Wilson et al.35 reported that perceived socialisolation predicted cognitive decline and risk forAlzheimer’s disease. Importantly, perceived isola-tion persisted in predicting each of these outcomeseven when social network size and frequency of so-cial activity were statistically held constant. Simi-larly, perceived isolation has been found to predictlifetime change in IQ36 and changes in depressivesymptomatology37,38 beyond what could be pre-dicted by objective isolation. Experimental manip-ulation of social isolation39and imagined future iso-lation40 result in cognitive and behavioral changeseven though objective isolation is not altered in theseexperimental studies. An experience sampling study,in which participants were beeped randomly ninetimes per day for seven days, confirmed that the so-cial interactions of individuals who feel isolated, incontrast to connected, were more negative and less

18 Ann. N.Y. Acad. Sci. 1231 (2011) 17–22 c© 2011 New York Academy of Sciences.

Cacioppo et al. Social isolation

satisfying, and such interactions contributed subse-quently to more negative moods and interactions.41

Perceived social isolation, known more collo-quially as loneliness, was characterized in earlyscientific investigations as “a chronic distress with-out redeeming features.”42 Recent research suggeststhat the social pain of loneliness evolved as a sig-nal that one’s connections to others are weakeningand to motivate the repair and maintenance of theconnections to others that are needed for our healthand well-being and for the survival of our genes.43

Physical pain is an aversive signal that evolved tomotivate one to take action to minimize damage toone’s body. Feeling socially disconnected and iso-lated triggers social pain, an aversive signal thatevolved to motivate one to take action that mini-mizes threats or damage to one’s social body. Re-search on social rejection, for instance, suggests thatsocial pain co-opted the physical pain to extend itsprotective function to include those with whom weform connections. In Eisenberger, Lieberman, andWilliams,44 participants were excluded from or in-cluded in a social situation (i.e., a ball tossing game).Results revealed neural activation localized in a dor-sal portion of the anterior cingulate cortex that isimplicated in the affective component of the phys-ical pain response. Eisenberger et al. suggest that,“Because of the adaptive value of mammalian socialbonds, the social attachment system. . . may havepiggybacked onto the physical pain system to pro-mote survival” (p. 291).

Open field behavior in nonhuman animals rep-resents a compromise between predator evasiontactics and the reinstatement of contact with aningroup.45,46 Evidence from behavioral and fMRIstudies suggests that social isolation increases atten-tion to negative social stimuli (e.g., social threats)as well as increased motivation to reconnect. Us-ing a modified emotional Stroop task, individualswho felt isolated, relative to those who felt con-nected, showed greater Stroop interference, specifi-cally for negative social relative to negative nonsocialwords.47 No differences were found in Stroop inter-ference for positive social relative to positive nonso-cial words. Stroop interference is used to gauge theimplicit processing of stimuli, so these results sug-gest that perceived isolation is associated with aheightened accessibility of negative social informa-tion. Similarly, Yamada and Decety48 investigatedthe effects of subliminal priming on the detection

of painful facial expressions. Using signal detectionanalyses, they found that although the pain wasmore easily detected in dislikable than likable facesoverall, lonely individuals were more sensitive (d′)to the presence of pain in dislikable faces than werenonlonely individuals.

In an fMRI study, we found that individual dif-ferences in perceived isolation predicted the acti-vation of the visual cortex to the presentation ofunpleasant social, in contrast to nonsocial, pictures,consistent with the remnants of greater predatorevasion and a stronger focus on self-preservation inindividuals who feel isolated. To examine this pos-sibility, activation in the temporoparietal junction(TPJ)—a region that has been found previously tobe activated in theory of mind tasks and in tasks inwhich individuals take the perspective of another—was also examined.47 TPJ activation was observedwhen participants viewed unpleasant pictures ofpeople versus objects and, as would be expectedif isolation increases a focus on predator evasionand self-preservation, individual differences in per-ceived social isolation were inversely related to theamount of activation observed in the TPJ.

We also investigated the extent to which indi-vidual differences in perceived isolation predicteddifferential activation of the ventral striatum topleasant social versus matched nonsocial images.47

The ventral striatum, a key component of themesolimbic dopamine system, is rich in dopamin-ergic neurons and is critical in reward process-ing and learning.49,50 The ventral striatum isactivated by primary rewards such as stimulantdrugs,51 abstinence-induced cravings for primaryrewards,52 and secondary rewards such as money.53

Evidence that social rewards also activate the ven-tral striatum has begun to accumulate in studies ofromantic love,54 social cooperation,55 social com-parison,56 and punitive altruism.57 We found thatperceived isolation predicted weaker activation ofthe ventral striatum to pleasant pictures of peoplethan of equally pleasant pictures of objects. Theseresults raise several interesting questions. As notedabove, an experience sampling study indicatedthat individuals who felt socially isolated regardpleasant interpersonal interactions as less pleasantthan do individuals who feel socially connected.41

Does perceived isolation modulate the responsive-ness of rudimentary reward systems to social andnonsocial stimuli, or do preexisting differences in

Ann. N.Y. Acad. Sci. 1231 (2011) 17–22 c© 2011 New York Academy of Sciences. 19


dopaminergic response to appetitive social andnonsocial stimuli lead to differences in social iso-lation? Although animal studies may be particularlyinformative, the finding that individual differencesin perceived social isolation are about 50% heritableincreases the plausibility of the latter hypothesis.

Heritability

That perceived isolation has an evolutionary basisis suggested by adoption and twin studies with chil-dren58,59 and with adults.60–62 These studies indicatethat the heritability of individual differences in per-ceived isolation is approximately 50%. We have in-terpreted this heritability as reflecting differences insensitivity to the pain of social disconnection.63 Butwhat evidence is there that this heritability reflects,at least in part, individual differences in sensitivityto social disconnection? Myron Hofer’s45 researchon the selective breeding of rats provides a provoca-tive case. A well-characterized response to maternalseparation is the separation cry. In the rat, the sep-aration cry is in the ultrasonic range (40–45 kHz).These ultrasonic vocalizations (USVs) to isolationare attenuated in a dose-related fashion by anxi-olytics that act on benzodiazepine and serotoninreceptors and are exaggerated by anxiogenics suchas the benzodiazepine receptor partial inverse ag-onist FG7142.64 Neuroanatomical studies reviewedby Hofer45 point to the periaquaductal gray area asa neural substrate for these USVs in rats and thehypothalamus, amygdala, thalamus, hippocampus,and cingulate cortex as the neural substrates for iso-lation calls in primates. As Hofer notes,

The evolution of such a response is clarified by thefinding that infant rat USV is a powerful stimulus forthe lactating rat, capable of causing her to interruptan ongoing nursing bout, initiate searching outsidethe nest, and direct her search toward the sourceof the calls . . . The mother’s retrieval response tothe pup’s vocal signals then results in renewed con-tact between pup and mother. This contact, in turn,quiets the pup.45

Hofer uses the concept of attachment to describethe emotional expression represented by the USVsand the reestablishment of the social bond by thematernal search for, renewed contact with, and com-fort response of the rat pup.

Although the infant USV helps guide the motherto their offspring, these USVs can also lead preda-

tors to the infant. USVs may be beneficial or dele-terious depending on the presence of predators inthe environment. As a consequence, no single levelof intensity of USVs to isolation is universally best,and heritable individual differences in this predis-position exist in the population. Some rat pups,who might be characterized as sensitive to sepa-ration, cry frequently (albeit ultrasonically) whenisolated, whereas others are less sensitive to sepa-ration and show less distress when isolated. Hoferand colleagues selectively bred adult rats that, asrat pups, showed either high or relatively low ratesof USVs to separation.65 After 25 generations of se-lective breeding, differences in behavior between thetwo lines of rats were reminiscent of some of the dif-ferences observed in humans who are high or lowin perceived isolation:22 the high, relative to low,USV line showed more distress to isolation as aninfant; greater latency to play as an adolescent; andgreater depression-like behaviors, greater anxiety-like behaviors, greater latency to social interactions,greater startle, and diminished learning as an adult.That is, the high USV line was anxious and passive,whereas the low USV line was exploratory, active,and aggressive.45 This work, then, suggests a linkbetween individual differences in perceived socialisolation and attachment processes and points toa specific aspect of the phenotype (sensitivity toisolation) and an evolutionary mechanism for thisphenotype. Note, however, that in this context themother–infant attachment builds on heritable dif-ferences in sensitivity to isolation rather than thepain of isolation resulting from poor infant attach-ment behaviors by the mother. Moreover, perceivedisolation in humans represents a complex pheno-type, so attachment may not represent its sole evo-lutionary basis.

Summary

Experimental, cross-sectional, and longitudinalstudies are beginning to elucidate the various waysin which perceived isolation is related to, and insome cases affects, human neural, hormonal, cellu-lar, and genetic processes. Early in our history as aspecies, we survived and prospered only by band-ing together—in couples, in families, in tribes—toprovide mutual protection and assistance. The painof (perceived) isolation evolved like any other formof pain. Indeed, there is now considerable evidencethat social isolation, and the pain associated with


Cacioppo et al. Social isolation

the disconnection that it produces, can fruitfully beconceived as a biological construct, a state that hasevolved as an aversive signal that motivates behav-ior changes to help individuals avoid damage andpromote the transmission of genes to the gene pool.In the case of isolation, the signal is a prompt to bealert to social threats (predator evasion) and to re-new the connections we need to survive and prosper.The effects of perceived isolation in humans sharemuch in common with the effects of experimen-tal manipulations of isolation in nonhuman socialspecies: increased sympathetic tonus and HPA acti-vation; glucocorticoid resistance; and decreased in-flammatory control, immunity, sleep salubrity, andexpression of genes regulating glucocorticoid re-sponses. The combination of immunosuppressionand proinflammatory effects may be especially caus-tic. Together, these effects contribute to higher ratesof morbidity and mortality in older adults.

Acknowledgments

This research was supported by National Instituteof Aging Grant No. RO1 AG034052–01.

Conflicts of interest

The authors declare no conflicts of interest.

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Social isolation